One of the most adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) is their ulcerogenic activity on the gastrointestinal tract. Flavonoids are shown to possess anti-inflammatory efficacy without the ulcerogenic side effects (Parmar N S, Ghosh M N. In Proceedings of the 6th Hungarian Bioflavonoids Symposium. Farkas L., et al. (Ed.), Elsevier, Amsterdam 513-516, 1981). Examples of those flavanoids and flavonoids are as listed in the recent review (Lin J-K, Tsai S-H, Lin-Shiau S-Y. Drugs of the Future 26: 145-152; 2001). Flavanoids, flavonoids, and isoflavones are shown to be effective inhibitors of angiogenesis, tumor growth and tumor metastasis (Igura K, Ohta T, Kuroda Y, Kaji K. cancer Lett. 171:11-16; 2001; Kimura Y, Okuda H. J Nutr. 131: 1844-1849; 2001; Lin J-K, Tsai S-H, Lin-Shiau S-Y. Drugs of the Future 26: 145-152; 2001). The recent marketing of two selective cyclooxygenase 2 (COX-2) inhibitors climaxes the first phase of an exciting and fast-paced effort to exploit a novel molecular target for nonsteroidal anti-inflammatory drugs (NSAIDs). Much has been written in the lay and scientific press about the potential of COX-2 inhibitors as anti-inflammatory and analgesic agents that lack the gastrointestinal side-effects of traditional NSAIDs. Although research on COX-2 inhibitors has focussed mainly on inflammation and pain, experimental and epidemiological data suggest that COX-2 inhibitors could be used in the treatment or prevention of a broader range of diseases. Recent reports suggested increased thrombogenicity of COX2-specific inhibitors (Catella-Lawson F, Crofford L J, Am J Med 110: p28S-32S; 2001) in high risk patients suggesting the need for an adjunct antiplatelet agent.
Antiplatelet therapy has become a standard treatment of acute and chronic arterial thrombotic diseases. Among current available anti-platelet drugs, aspirin is the drug of choice for secondary prevention of myocardial infarction (Schror K. Antiplatelet drugs. Drugs 50:7-28, 1995). Its antiplatelet activity is mainly due to the irreversible inhibition of the platelet cyclo-oxygenase causing a last-lasting blockade of platelet-dependent thromboxane A2 formation. Since pro-inflammatory stimuli might trigger the extension of thromboembolic disorders and vice versa, the combination of standard dose of COX2 inhibitors (anti-inflammatory) and aspirin (antiplatelet+limited anti-inflammatory) at the 70-85 mg would improve the efficacy and safety of each other. Additionally, COX2 inhibitors similar to the flavanoids exhibited anti-angiogenesis and anti-tumor efficacy. Recent studies demonstrated overexpression of COX-2 in multiple human tumors and pharmacological evidence in animal models, which indicate that COX-2 inhibitors could be used in the prevention or treatment of a broader range of disease (Kalgutkar A S, Zhao Z. Curr Drug Targets. 2(1): 79-106, 2001).
Compared with traditional non-steroidal anti-inflammatory drug agents, use of COX-2 selective inhibitors is associated with decreased incidence of adverse gastric events as a result of minimal inhibition of gastroprotective COX-1, but with equivalent anti-inflammatory benefit through inhibition of COX-2 . However, there is evidence to suggest that the ‘COX-1=constitutive, COX-2=inflammatory’ paradigm is less distinct than originally proposed. Furthermore, selective COX-2 inhibitors may have other consequences as a result of the change in the eicosanoid profile. Thus, despite the relatively safe gastrointestinal profile, vigilant post-marketing surveillance for other adverse effects is required (Penglis P S, James M J, Cleland L G., Intern Med J 2001;31(1):37-41). In that regard, recent clinical reports suggested increased thrombotic events in patients taking COX2 inhibitors suggesting the urgent need for the use of the COX1 inhibitory efficacy of aspirin to improve such serious adverse outcome when using COX2 inhibitors for long term.
The recent marketing of two selective cyclooxygenase-2 (COX-2 ) inhibitors, celecoxib and rofecoxib is remarkable considering that COX-2 was only discovered eight years ago as a growth factor- and cytokine-inducible gene. Concomitant with these pharmaceutical successes is the advances in our understanding of the molecular and structural basis for selective COX2 inhibition. In addition to the existing inhibitor classes, there are many novel structural classes which have recently emerged due to a better understanding of the active site differences between the two isozymes (Kalgutkar A S, Zhao Z., Curr Drug Targets 2001; 2(1): 79-106). In addition to its role in inflammation, recent studies suggest that COX-2 -derived prostaglandin may play a pivotal part in the maintenance of tumor viability, growth, and metastasis. NSAID epidemiological evidence, studies demonstrating overexpression of COX-2 in multiple human tumors and pharmacological evidence in animal models, which indicate that COX-2 inhibitors could be used for the prevention or treatment of a broader range of disease.